An osteosarcoma (OS) model in which the number of tumor cells can be quantitatively measured in individual animals with the serum alkaline phosphatase (AP) levels has been developed. The tumor is radiation and chemotherapy resistant and poorly antigenic. It rapidly metastasizes to the lungs when the tumor is implanted i.m. into the leg. These characteristics of the tumor present all of the problems associated with the clinical situation faced by oncologists. We believe application of current modes of treatment augmented with new systemic treatment modality when employed in the proper sequence and combinations can bring about therapeutic cures in animals with extensive metastatic diseases. This model has been used to assess the effects of combinations of surgery, chemotherapy, irradiation, hyperthermia and specific and nonspecific immunotherapy. None of these modes singly or in combination appear effective against the rapidly metastasizing OS which is chemotherapy and radiation resistant. Moreover, the poor antigenic quality of OS makes immunotherapy inadequate in the syngeneic tumor-bearing mice. Our studies show combination treatment is better, but produces almost no cures if treatment is late. New studies are proposed to concentrate on systemic modes of treatment. The new modes involve either alteration of the host to make the host more resistant to its syngeneic neoplasm or to alter the tumor in vivo to make the tumor more susceptible to current modes of treatment. The procedure of adult thymectomy (ATx) and restoration of effector functions by thymic hormone (TH) or 2-mercaptoethanol (2-ME) treatment are the primary means of host alteration which will be tested. Attempts to alter the functions of the tumor will be made with homoarginine, dichloromethylenediphosphonate (Cl2MDP) and misonidazole.